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ISSN 0975-413XCODEN Der Pharma Chemica, 2017, 9(8):55-58 (USA): PCHHAX (http://www.derpharmachemica.com/archive.html)

An Efficient Synthesis of β-Enaminoketone/Ester Under Grinding Condition Using Bromide as Solid Support Catalyst

Pramod Kulkarni*, Ajay Jadhav

Department of Chemistry, Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune, Maharashtra, 410505, India

ABSTRACT

Calcium bromide was used as a catalyst in the synthesis of β-enaminoketone/ester from 1,3-dicarbonyl compound and amines. The reaction was carried out in mortar and pestle at room temperature. The process is mild, efficient, eco-friendly and cost-effective with the use of very small amount of catalyst; avoiding use solvent, simple product separation, and high yield. We compare this grinding reaction condition with reaction in solvent and we got better results with the grinding reaction condition.

Keywords: Calcium bromide, β-Enaminoketone, Solvent free, Grindstone Chemistry, Green synthesis

INTRODUCTION

Solid-state chemistry has been developed rapidly as a competent and selective method, since molecules in the crystals have been arranged tightly and regularly. One of the methods belonging to this etiquette is a simple grinding method called a grindstone (mechanochemical) method which reactants are ground simply by mortar and pestle. Grinding is attracting many organic chemists due to it is performed in the absence of solvent, leading to safe and environmentally friendly synthesis. In addition to this, the proposed technique does not require external heating, leading to energy efficient synthesis and may be regarded as more cost-effective and ecologically favourable procedure in chemistry. Mechanical-induced breaking of molecular bonds, reduction of particle size, increase in surface area, formation of defects and local melting occur due to the kinetic energy supplied during grinding in solvent-free organic reactions based on grinding. The conveyance of very low measures of energy through friction in this operation leads to more efficient mixing and close contact between the starting materials on a molecular scale [1].

β-enaminones and β-enamino esters have been widely used as crucial intermediates in organic synthesis due to its variable nature as electrophiles and nucleophiles [2]. Enaminones are widely used as versatile building blocks for synthesis of important bioactive heterocyclic compounds and different biological active compounds [3]. Due to the broad range of pharmaceutical activity and key intermediate in organic synthesis create great interest of organic chemist to synthesize this molecule. The well-known route for the synthesis of β-enamino ketones and esters involves the direct condensation of β-dicarbonyl compounds with amines under reflux in an aromatic solvent with azeotropic removal of water [4]. A variety of catalysts such as metal [5-8], metal triflate [9-12], solid supported reagent [13-16], metal oxide [17,18], Bi(TFA)3 [8], β- cyclodextrin in water [19], VO(acac)2 [20], Ceric ammonium nitrate [21], [(PPh3)AuCl]/AgOTf [22], Ionic liquid promoted [23], Zn(ClO4)2.6H2O [24], trimethylsilyl trifluoromethane sulphonate (TMSTf) [25], Tris(Hydrogensulfato)Boron or trichloroacetic acid [26], Microwave assisted [27], Microwave radiation/K-10 [28], Phosphomolybdic acid (PMA) [29], K-10/Ultrasound [30], formic acid [31].

However, some of these methods have synthetic shortcomings such as use of expensive or combinations of catalysts, use of toxic solvent, longer reaction times, use of excess amount of catalyst, low yield, tedious work-up procedures, lack of selectivity, in some cases catalyst preparation requires, use of toxic metal catalysts. Therefore, there is scope to develop a new and efficient method for synthesis of β-enamination of 1,3- dicarbonyl compounds.

Calcium bromide is obtained by the interaction of and milk of the lime in the presence of ammonia. It is readily soluble in water and absolute [32]. It is thermally and chemically stable. Use of calcium bromide in organic synthesis is very rare [33,34]. Herein, we report the use of calcium bromide as a catalyst for the synthesis of β-enaminoketone/ester under solvent free condition.

EXPERIMENTAL SECTION General

All chemicals were purchased from Loba chemicals, Merck, Sigma Aldrich and used without further purification. Commercially available Calcium bromide is used as a catalyst and it is purchased from Loba chemicals. Melting points were determined by open capillary method and are uncorrected. All products are known and their structure is confirmed by Infra-red (IR), Proton Nuclear Magnetic Resonance (1HNMR), Carbon-13 Nuclear Magnetic Resonance (13CNMR), High Resolution Mass Spectrometry (HRMS) and comparison of this spectral data with those reported in the literature. Progress of the reaction was monitored by Thin Layer Chromatography (TLC) on precoated silica gel 60 F254 sheets.

55 Pramod Kulkarni et al. Der Pharma Chemica, 2017, 9(8):55-58

General experimental procedures for synthesis of β-enaminones

Method A: In a mortar and pestle, equimolar amounts of primary amines (1 mmol) and β-dicarbonyl compound (1 mmol) along with calcium bromide (2 mol%, 0.02 mmol, and 0.0047 g) as a catalyst were placed. The reaction mixture was continuously grinded for the specified time as given in Tables 1 and 2. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and product was extracted with ethyl acetate (2 × 15 ml) and washed with water and brine solution. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using ethyl acetate-petroleum ether (2:8 v/v). All products are known and their structure is confirmed by IR, 1HNMR, 13CNMR and HRMS. Table 1: Synthesis of β-enaminoketones and β-enamino esters using calcium bromide under solvent free grinding conditiona

Time (min) (%) Yieldb Entry β-dicarbonyl compounds Amines Product (3) M.P. [Ref] Under grinding In solvent Under grinding In solvent 1 Acetylacetone Aniline 3a 25 120 97 89 45-47 [17] 2 Acetylacetone 4-methylaniline 3b 22 90 92 83 66-68 [16] 3 Acetylacetone 4-chloroaniline 3c 27 85 90 81 61-62 [16] 4 Acetylacetone 4-nitro aniline 3d 55 300 87 78 141-143 [17] 5 Acetylacetone 4-methoxyaniline 3e 30 74 94 83 45-46 [16] 6 Acetylacetone o-nitroaniline 3f 120 360 No reaction No reaction - 7 Acetylacetone 2-methyl aniline 3g 65 240 74 57 38-40 [4] 8 Acetylacetone 2-methoxyaniline 3h 75 280 58 47 Oil [18] 9 Acetylacetone methyl amine 3i 20 82 84 74 46-48 [23] 10 Acetylacetone butyl amine 3j 25 78 87 78 Oil [16] 11 Ethyl acetoacetate Aniline 3k 30 105 92 82 Oil [16] 12 Ethyl acetoacetate 4-methyl aniline 3l 24 94 88 81 Oil [16] 13 Ethyl acetoacetate 4-methoxy aniline 3m 20 68 90 80 47-48 [16] 14 Ethyl acetoacetate 4-chloro aniline 3n 38 130 83 73 56-58 [16] 15 Ethyl acetoacetate 4-bromo aniline 3o 45 170 81 72 53-56 [18] 16 Ethyl acetoacetate 1-naphthylamine 3p 55 200 74 61 Oil [18] 17 Ethyl acetoacetate benzyl amine 3q 50 240 78 70 Oil [26] 18 Ethyl acetoacetate 2-methyl aniline 3r 67 265 58 50 Oil [4] 19 Ethyl acetoacetate butyl amine 3s 30 110 73 59 Oil [22] 20 Ethyl acetoacetate 2-nitro aniline 3t 120 360 No reaction No reaction - 21 1-phenylbutane-1,3-dione Aniline 3u 75 210 78 71 107-109 [31] 22 1-phenylbutane-1,3-dione 4-methoxy aniline 3v 50 240 81 74 92-95 [31] 23 1-phenylbutane-1,3-dione 4-methyl aniline 3w 54 200 85 77 86-87 [31] 24 1-phenylbutane-1,3-dione 4-chloroaniline 3x 63 260 82 74 127-129 [31] a: Reaction conditions: Method A in mortar and pestle and Method B with stirring in Ethanol amine (1 mmol) and β-dicarbonyl compound (1 mmol) and calcium bromide (2 mol %, 0.0 2 mmol) were placed b: isolated yield

Method B: To a mixture of β-dicarbonyl compound (1 mmol) and primary amines (1 mmol) in ethanol (5 ml), calcium bromide (2 mol%, 0.02 mmol, 0.0047 g) was added at room temperature with stirring. The reaction mixture was stirred for the specified time as given in Tables 1 and 2. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and product was extracted with ethyl acetate (2 × 15 ml) and washed with water and brine solution. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using ethyl acetate- petroleum ether (2:8 v/v).

Table 2: Synthesis of cyclic β-enaminoes using calcium bromide under solvent free grinding conditiona

Time (Min) % Yieldb β-dicarbonyl Entry Amines Product (4) Under M. P.[Ref] compounds Under grinding In solvent In solvent grinding 1 Dimedone aniline 4a 45 125 92 86 185-186 [16] 2 Dimedone 4-chloroaniline 4b 53 160 86 80 192-194 [26] 3 Dimedone 4-bromoaniline 4c 60 194 82 79 220-221 [16] 4 Dimedone 4-methoxy aniline 4d 40 135 91 85 193-195 [16] 5 Dimedone 4-nitroaniline 4e 75 250 78 70 192-193 [26] 6 Dimedone 2-methoxy aniline 4f 85 300 63 57 125-127 [16] 7 Dimedone 3-nitro aniline 4g 70 256 82 76 168-170 [26] 8 Dimedone 2-nitroaniline 4h 120 360 No reaction No reaction - 9 Dimedone benzyl amine 4i 65 175 77 73 127-128 [16] 10 Dimedone butyl amine 4j 65 182 86 79 117-119 [16] a: Reaction conditions: Method A in mortar and pestle and Method B with stirring in Ethanol amine(1 mmol) and β-dicarbonyl compound (1 mmol) and calcium bromide (2 mol%, 0.02 mmol) were placed b: isolated yield

RESULTS AND DISCUSSION

The condensation of aniline and acetyl was selected as a model reaction. Initially we have various metal salts such as , ferric sulphate, , magnesium chloride, calcium bromide, calcium carbonate, calcium nitrate, magnesium nitrate, magnesium sulphate, as catalyst for the condensation reaction under solvent free grinding condition and results are summarized in table (Table 3). The model reaction is performed using 1 mmol of aniline, 1 mmol of acetyl acetone and 0.2 mmol of catalyst in mortar and pestle. From Table 3 it was observed that calcium bromide was found an efficient catalyst for synthesis of β-enaminoketone/ester with 97% yield. Calcium sulphate, magnesium sulphate, calcium carbonate, ferric sulphate did not give the desire product.

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Table 3: Screening of catalyst for condensation reaction between acetyl acetone and aniline under solvent free grinding conditiona

S. No. Catalyst Product Time (min) % Yieldb 1 CaCl2 3a 75 83 2 MgCl2 3a 90 85 3 SrCl2 3a 135 76 4 BaCl2 3a 140 72 5 CaBr2.2H2O 3a 25 97 6 MgBr2 3a 40 91 7 Ca(NO3)2 3a 55 75 8 Mg(NO3)2 3a 74 72 9 CaSO4.2H2O 3a 180 No reaction 10 MgSO4 3a 180 No reaction 11 CaCO3 3a 180 No reaction 12 Fe2(SO4)3 3a 180 No reaction a: Reaction conditions are: 1 mmol of aniline, 1 mmol of acetyl acetone and 0.2 mmol of catalyst under solvent free grinding condition; b: isolated yield after purification

Similarly, aniline (1 mmol) and acetylacetone (1 mmol) were selected as the model substrates to optimise the amount of calcium bromide. The catalyst loading was optimized by increasing the amount of calcium bromide from 0.5-20 mol% for 1 mmol scale reaction. The yield increased with the increase in catalyst amount (Table 4, entries 1-5). Nevertheless, there was a very minor increase in the yield when the catalyst loading has increased from 2-20 mol%. From table it was observed that 2 mol% of the catalyst was sufficient to obtain the best yield. Although reaction has also well proceeded with 0.5 mol% and 1 mol% of catalyst, but to achieve good yields, long reaction times were usually required to achieve yields comparable with those obtained with 2 mol% of catalyst (Table 4, entries 1-2).

Table 4: Optimising amount of catalysts for synthesis of β-enaminoketonea

Entry Catalyst/Mol% Time (Min) % yieldb 1 0.5 65 74 2 1 52 83 3 2 25 97 4 5 20 97 5 10 20 95 6 15 20 96 7 20 20 94 a: Acetyl acetone (1 mmol) and aniline (1mmol) were used b: Isolated yield after purification

To study generality and scope of our methodology, the reaction was examined with calcium bromide (2 mol %) under solvent free grinding condition at room temperature. First we studied the scope of the reaction with various substituted aromatic and aliphatic primary amines with acetyl acetone and ethyl acetoacetate as shown in Figure 1. The results are displayed in Table 1. Table 1 showed that the reactions proceeded smoothly and with high yields were obtained. It was also observed that aromatic amines with electron donating substitutents or halogen substituents required a shorter reaction time than aromatic amines with electron-withdrawing groups. Additionally, the reaction with aliphatic amines proceeded readily requiring a shorter time than that required for the reaction with aromatic amines.

O O R' 2mol% CaBr2.2H2O NH O R'NH2 R Method A or B R 2 1 3

R- Me , Ph or -OEt R'-Aliphatic Aromatic Method A : Grinding in mortar and pestle Method B: Reaction is stirred in EtOH solvent

Figure 1: Synthesis of β-enaminoketones and β-enamino esters using calcium bromide under different condition

Also, this method was extended for preparation of cyclic β-enaminoketones under the same reactions conditions. The cyclic β-diketone reacted with various substituted primary aromatic amines as shown in Figure 2. Similarly aromatic amines with electron-donating substituents also required a shorter reaction time than aromatic amines with electron-withdrawing groups.

57 Pramod Kulkarni et al. Der Pharma Chemica, 2017, 9(8):55-58

O O 2mol% CaBr2. 2H2O

R'NH2 Method A or B NH O R 2 1 4

Method A : Grinding in mortar and pestle Method B: Reaction is stirred in EtOH solvent Figure 2: Synthesis of cyclic β-enamioes and β-enamino esters using calcium bromide under different condition

Consequently, it was found that all amines reacted only at the methyl ketone carbonyl for β-dicarbonyl compounds and β-ketoester. Also, β- dicarbonyl compounds and β-ketoester gave (Z)-β-enamino ketones and esters whereas the cyclic diketones give solely (E)-β-enamino ketones. The Z-form configuration of the products was confirmed by 1HNMR analysis. The proton of the-NH group appearing in a lower field (δ > 8.0) indicated formation of the intramolecular hydrogen bond which stabilized the products.

In summary, we have developed a simple, efficient and environmentally benign method for synthesizing β-enamino ketones and esters using a neutral and readily available catalyst calcium bromide under solvent free condition using grinding technique. The advantages of this method is high yield, easily available, non-toxic and inexpensive catalyst, short reaction time, low amount of catalyst is required to carry out the reaction, applicable to wide variety of substrates, avoiding use of solvent and finally conformity with green chemistry principles Table 5.

Table 5: Comparison of the result of synthesis of β-enaminoketones in presence of different catalysts

Entry Catalyst Catalyst loading Conditions Time (min) (%) Yield Ref 1 InBr3 0.05 mmol Solvent free, R.T. 50 98 [4] 2 CoCl2.6H2O 0.25 mmol, 0.0058 g R.T. 50 95 [5] 3 Bi(TFA)3 0.05 R.T./H2O 5-180 63-98 [8] 4 Er(OTf)3 1 mol% CH2Cl2/R.T. 120-360 71 [10] 5 P2O5/SiO2 30% w/w Solvent free 80°C 120 Good to excellent [13] 6 CAN 20 mol% CH3CN/R. T. 72-93 [21] [(PPh )AuCl]/ 7 3 0.03 mmol/ 0.03 Solvent free, R.T. 2- 5 70-98 [22] AgOTf 8 Silica sulfuric acid 0.4 g Solvent free 80°C 10 89 [16] 9 Tris(Hydrogensulfato)Boron 10% 120°C 7-10 75-85 [26] In this 10 CaBr .2H O 2 mol% 0.0047 g R.T. 25-120 97 2 2 paper 11 B2O3/Al2O3 15 mmol (0.03 g) Solvent free, R.T. 60 95 [18] 12 Silica supported Fe(HSO4)3 0.25 mmol, 0.22 g Solvent free, R.T. 7-40 60-95 [15] 13 Phosphomolybdic acid 1 mol% CH3CN/R.T. 1-3 h Good to excellent [29]

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